Prior infection of cells with one retrovirus often renders them resistant to "super-infection" with another retrovirus. The resistance is thought to arise because viral envelope protein produced in the infected cell interacts with receptor, rendering it incapable of interacting normally with incoming viruses. A similar mechanism may be responsible for certain forms of inherited resistance to retroviruses in animal systems in which the resistance is co-inherited with an expressed, "endogenous" retroviral envelope gene. One such endogenous retroviral envelope gene in mice genetically linked to a resistance trait (Fv-4) was cloned in LMM several years ago. To investigate the in vivo effects of this gene, we generated transgenic mice in which the Fv-4 envelope gene is driven by its associated flanking cellular promoter. Two transgenic strains were obtained. Southern blot analysis and genetic breeding experiments showed that each strain contains a transgene in a single (and distinct) location in the mouse genome. Northern blot analysis showed that the transgenes are expressed to high level in relevant lymphoid tissues. Susceptibility to retroviral infection in vivo was assayed by inoculating mice with Friend virus and scoring splenomegaly and spleen virus titer at various times after infection. Both transgenic mouse strains were markedly resistant to infection as assayed by XC test, although at high doses of inoculum some transgenic mice developed splenomegaly, indicating that the resistance was not absolute. This model of natural resistance to retroviruses could form the basis of "gene therapy" approaches to HIV. We are investigating the effects of placing other potential retroviral resistance genes, including the HIV envelope, downstream of the FV-4 promoter in tissue culture and transgenic systems.